1. Field of the Invention
The invention relates to organic compounds and pharmaceutical preparations thereof which are suitable for the regulation of vectorial ion channels, of diseases associated with the lung function and for the treatment of oedemas.
2. Description of the Prior Art
The fluid transport through cell layers and tissue is primarily based on an osmotic gradient by a vectorial ion transport, e.g., sodium transport. It is accomplished mainly by strictly regulated and vitally important ion channels such as, e.g., the epithelial sodium channel complex (ENaC) (Ware L. B. and Matthay M. A. New England J Med 2001; 342/18: 1334-1359. Matthay et al., Am J Physiol 1996; 270:L487-L503; Berthiaume Y. and Matthay M. A. Respiratory Physiology & Neurobiology 159 (2007) 350-359). Water passively follows this gradient, inter alia, through special water channels such as the water channel Aquaporin V. Therefore, a medicinal regulation of the vectorial ion transport through cells and tissue would result in the possibility of controlling the fluid content of tissues as well as of preventively or therapeutically treating diseases which are associated with an accumulation of fluid in the tissue.
If an oedema is mentioned, a pathological accumulation of fluid in an organ such as, e.g., in the lungs, but also in the brain or in the skin, is meant. An oedema in the lungs is called a pulmonary oedema. The pulmonary oedema is mostly based on an imbalance between fluid extravasation and fluid resorption. Very often, the permeability of the lung tissue is also damaged so that an increased fluid supply occurs and the fluid accumulates in the pulmonary alveoli.
A pulmonary oedema as a result of a lack of return transport of fluid from the pulmonary alveoli into the interstice is particularly significant for an Acute Lung Injury, ALI, for the Acute Respiratory Distress Syndrome, ARDS, for the Severe Acute Respiratory Syndrome (SARS), for pneumonia, for influenza and for other bacterially and virally induced lung diseases. However, the pulmonary oedema also plays a significant part in other lung diseases such as respiration-induced lung injuries, lung transplants, transfusion-associated lung injuries, therapeutical administration of IL-2 or asthma.
As a result of an increased fluid accumulation in the tissue or organ, e.g., in the lungs, the required gas exchange is impeded or completely restricted. No oxygen from the breathing air reaches the blood so that life-threatening organ damages may occur due to oxygen deficiency.
Lucas et al (Lucas R et al. Science 1994, 263: 814) describe a peptide which is derived from the regions Ser(99) to Glu(116) of the tumour necrosis factor and is supposed to control the fluid content in the pulmonary alveoli.
Said peptide comprising the sequences SEQ ID NO: 10 CGQRETPEGAEKPWYC is also the subject matter of WO00/09149.
A peptide also for controlling the fluid content in the alveoli and comprising the sequence SEQ ID NO: 11 CGTKPIELGPDEPKAVC is included in EP 2 009 023, and a peptide comprising the sequence SEQ ID NO: 12 LSPGQRETPEGAEAKPWYE is included in WO2009/073909.
So far, there has been no selective and medically usable therapy or treatment for the regulation of vectorial ion channels in cells and tissues, in particular for the regulation of vectorial ion channels of the lung tissue. Neither has there been so far a selective therapy for the regulation of the vectorial ion transport in the lungs and in particular for the treatment of pulmonary oedemas. Quite generally, it is attempted to give artificial respiration to patients suffering from pulmonary oedemas in order to ensure the supply of oxygen to the blood and thus to the organs.